Colocalization analysis of polycystic ovary syndrome to identify potential disease-mediating genes and proteins

Eur J Hum Genet. 2021 Sep;29(9):1446-1454. doi: 10.1038/s41431-021-00835-8. Epub 2021 Mar 4.


Polycystic ovary syndrome (PCOS) is a common complex disease in women with a strong genetic component and downstream consequences for reproductive, metabolic and psychological health. There are currently 19 known PCOS risk loci, primarily identified in women of Han Chinese or European ancestry, and 14 of these risk loci were identified or replicated in a genome-wide association study of PCOS performed in up to 10,074 cases and 103,164 controls of European descent. However, for most of these loci the gene responsible for the association is unknown. We therefore use a Bayesian colocalization approach (Coloc) to highlight genes in PCOS-associated regions that may have a role in mediating the disease risk. We evaluated the posterior probabilities of evidence consistent with shared causal variants between 14 PCOS genetic risk loci and intermediate cellular phenotypes in one protein (N = 3301) and two expression quantitative trait locus datasets (N = 31,684 and N = 80-491). Through these analyses, we identified seven proteins or genes with evidence of a possibly shared causal variant for almost 30% of known PCOS signals, including follicle stimulating hormone and ERBB3, IKZF4, RPS26, SUOX, ZFP36L2, and C8orf49. Several of these potential effector proteins and genes have been implicated in the hypothalamic-pituitary-gonadal signalling pathway and provide an avenue for functional follow-up in order to demonstrate a causal role in PCOS pathophysiology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Humans
  • Ikaros Transcription Factor / genetics
  • Oxidoreductases Acting on Sulfur Group Donors / genetics
  • Polycystic Ovary Syndrome / genetics*
  • Polycystic Ovary Syndrome / metabolism
  • Proteome / genetics
  • Proteome / metabolism
  • Quantitative Trait Loci*
  • Receptor, ErbB-3 / genetics
  • Ribosomal Proteins / genetics
  • Transcription Factors / genetics


  • IKZF4 protein, human
  • Proteome
  • RPS26 protein, human
  • Ribosomal Proteins
  • Transcription Factors
  • ZFP36L2 protein, human
  • Ikaros Transcription Factor
  • Oxidoreductases Acting on Sulfur Group Donors
  • SUOX protein, human
  • ERBB3 protein, human
  • Receptor, ErbB-3